Human body temperature is normally maintained at about 37° C. However, the body temperature decreases when the function of the central nervous system (and, thus, the temperature regulatory center) is decreased by general anesthesia performed during surgical operations. The result is often hypothermia.
Hypothermia causes complications including chillness/discomfort, shivering, tachycardia/ischemic change in ECG, delayed emergence, wound infection, delayed healing of wounds, decreased immune activity and blood coagulation disorder.
Hypothermia ultimately leads to delayed postoperative recovery and decreased immune activity, increasing the risk of complications. Also, hypothermia during anesthesia is one of the factors that cause delayed awakening from anesthesia. For these reasons, prevention of hypothermia during surgical operations is medically important.
To prevent this type of hypothermia, various measures are taken in medical fields to keep patients warm during surgical operations, including aluminum heat-insulating materials, heat circulatory mats, warmed infusion fluids and heating with warm air streams. However, conventional heat circulatory mats can only warm part of a patient's body depending on the body position of the patient and thus have limited effectiveness in keeping patients warm. Heating with warm air streams is effective but costly since it requires warming covers, which cover patients, and other supplies.
Furthermore, any of the conventional approaches for keeping patients warm takes long to raise the body temperature back to normal levels once the body temperature has decreased beyond the threshold below which the temperature center can no longer return the body temperature to the normal levels.
Several recent studies have reported that a total amino acid infusion fluid preparation containing high concentrations of amino acids (total amino acid concentration=10 w/v % or higher) are effective in preventing hypothermia (Non-Patent Documents 1 to 3). An anti-hypothermia composition containing amino acids has also been proposed (Patent Document 1).
In the course of our studies of postoperative awakening from anesthesia, the present inventors have found that awakening from anesthesia is accelerated in patients receiving a perioperative infusion fluid containing a bicarbonate ion during the perioperative (intraoperative) period, as compared to patients receiving a perioperative infusion fluid containing sodium acetate or sodium lactate. Based on this finding, the present inventors have proposed an anesthesia arousal composition that contains a bicarbonate ion as an electrolyte (Patent Document 2).
The present inventors conducted studies to examine the relationship between acidosis and the time it takes for patients to awaken from anesthesia using a rat model with partial liver excision as well as a rat model of streptozotocin (STZ)-induced diabetic ketoacidosis. The present inventors also conducted studies to examine the ability of bicarbonated-Ringer's solution to facilitate recovery (awakening time) after anesthesia using a rat model with partial kidney excision. These studies have revealed that the time to awakening from anesthesia is significantly shorter in patients receiving the bicarbonated-Ringer's solution as compared to patients receiving the acetated-Ringer's solution or the lactated-Ringer's solution.
One reason for this is believed to be that the changes in the plasma concentration of an anesthetic and thus, the rate at which the anesthetic is metabolized by the liver, differ depending on the type of Ringer's solution. It has been suggested that this difference results from the difference in the ability of each Ringer's solution to correct acidosis. Another reason for the accelerated awakening time is believed to be the difference in the protein binding of propofol among the different Ringer's solutions.
Thus, the bicarbonated-Ringer's solution that contains sodium bicarbonate rather than sodium acetate or sodium lactate (alkalizers used in the conventional Ringer's solution) can directly correct acidosis since its alkalization effect does not involve the metabolic pathway of sodium acetate or sodium lactate.
According to the study conducted by the present inventors to examine the time to awakening from anesthesia in animal models of different metabolic diseases, the time to awakening from anesthesia is inversely related to the blood pH: the more severe acidosis is, the more delayed the emergence from anesthesia will be. This observation suggests that quick correction of acidosis accelerates awakening of patients from anesthesia, thus facilitating the postoperative recovery of the patients.
It has been observed that patients receiving the bicarbonated-Ringer's solution during the surgery have less risk of developing hypothermia than those receiving other types of extracellular fluid replacement (for example, acetated-Ringer's solution).
The present inventors hypothesized that the reduced risk of hypothermia in patients administered the bicarbonated-Ringer's solution was due to the ability of the bicarbonated-Ringer's solution to correct acidosis and to prevent the decrease in the biological function. To verify this hypothesis, the present inventors conducted a study using a normal rat model and a rat model of STZ-induced diabetic ketoacidosis to determine whether or not the bicarbonated-Ringer's solution is more effective in the prevention of hypothermia during anesthesia than the acetated-Ringer's solution or the official Ringer's solution (prepared according to Japanese Pharmacopoeia) and, if so, to what degree.
The study showed that, in normal rats, the body temperature remained at the same level in the bicarbonated-Ringer group and in the acetated-Ringer group. The body temperature of these two groups showed a tendency to be higher than that of the Ringer group, though no significant differences were observed between the two groups and the Ringer group.
Normal rats generally develop hypothermia, but not acidosis, when put under anesthesia Also, none of the studied official Ringer's solution, the bicarbonated-Ringer's solution and the acetated-Ringer's solution contained any components that serve as an energy source (carbohydrate, amino acids and fats).
Since the bicarbonated-Ringer's solution and the acetated-Ringer's solution have electrolyte compositions more close to physiological state than the official Ringer's solution, the bicarbonated-Ringer's solution and the acetated-Ringer's solution are more effective in maintaining circulatory kinetics and homeostasis than the official Ringer's solution.
In normal rats, these differences are considered to be the cause of the difference in the degree of hypothermia between the group receiving the bicarbonated-Ringer's solution or the acetated-Ringer's solution and the group receiving the official Ringer's solution.
In diabetic rats, the body temperature remained higher in the bicarbonated-Ringer group than in the acetated-Ringer group and official Ringer group. Also, the change in the body temperature before the termination of anesthetic was significantly smaller in the bicarbonated-Ringer group than in the acetated-Ringer group and the official Ringer group.
Diabetic rats generally develop significant acidosis with a blood pH of 7.2 (ketoacidosis). As reported in the non-patent document 4, in ketoacidosis, the alkalization effect of sodium acetate becomes less significant because the metabolism of ketone bodies produced in large quantities in ketoacidosis interferes with the metabolism of sodium acetate.
Unlike sodium acetate, an alkalizer used in the acetate-Ringer's solution, sodium bicarbonate used as an alkalizer in the bicarbonated-Ringer's solution can supply bicarbonate ion without being involved in the metabolism. Thus, it can be used as an effective alkalizer in patients with metabolic disorder and organ dysfunction to correct acidosis and maintain a high blood pH that is difficult to achieve by the use of the other Ringer's solutions.
In summary, the studies conducted by the present inventors have proven that the difference in the degree of hypothermia among the groups administered the bicarbonated-Ringer's solution, the acetated-Ringer's solution and the official Ringer's solution is mainly due to the fact that the ability of a Ringer's solution to prevent hypothermia varies depending on whether or not an alkalizer is present in the Ringer's solution, or, if it is present, the type of the alkalizer.
Since the bicarbonated-Ringer's solution and the acetate-Ringer's solution have compositions more close to physiological state than the official Ringer's solution, these solutions can suppress the decrease in the biological function caused by anesthesia and, thus, the resulting hypothermia. This is an advantage that cannot be achieved by the administration of the official Ringer's solution. The bicarbonated-Ringer's solution, which can provide alkalization effect without requiring the metabolism, can bring about the alkalization effect faster than the acetated-Ringer's solution. For this reason, the bicarbonated-Ringer's solution can correct acidosis faster than the acetated-Ringer's solution in patients with diseases associated with acidosis. As a result, the decreased biological function due to acidosis can recover quickly, which helps keep the body temperature high.
The present invention has been devised based on the foregoing knowledge.
Patent Document 1: International Patent Publication No. WO2004/096267
Patent Document 2: PCT/JP 2006/310671
Non-Patent Document 1: Anesh. Analg. 89: 1551-1556, 1999
Non-Patent Document 2: Japanese Journal of Surgical Metabolism and Nutrition 36(4): 215-220, 2002
Non-Patent Document 3: British J. of Anaesthesia 90: 58-61, 2003
Non-Patent Document 4: Pharmaceutical Regulatory Science 28(9): 664-672, 1997